Guanidated aminophosphonic acid compounds

ABSTRACT

Novel guanidated aminophosphonic acid compounds their use as biocides and their intermediates. The compounds are guanidated N-(aminoalkyl) aminoalkanephosphonic acid derivatives and are characterized in that they comprise both a phosphonic acid type group and at least one guanidino group and also in that they are based on alkylene amines. The compounds have the general formula: ##STR1## wherein Z and Z&#39; are hydrogen, a lower alkyl group or an alkali metal, Y is hydrogen or an amidine group, m is 1-3, n is 4-16 and p is 1-3. The compounds can be prepared by reacting a halogenoalkanephosphonic acid compound with an alkylene di- or polyamine followed by guanidation of the so obtained product. The compounds are particularly useful as fungicides and especially as fungicides for industrial purposes.

The present invention relates to novel guanidated aminophosphonic acidcompounds and to the use of these compounds as biocides. The inventionfurther relates to a process for the preparation of the guanidatedaminophosphonic acid compounds and to novel aminophosphonic acidcompounds useful as intermediates in this process.

The novel compounds of the invention have the general formula ##STR2##wherein Z and Z', which may or may not be equal, are hydrogen, a loweralkyl group having 1 to 4 carbon atoms or an alkali metal, Y is hydrogenor an amidine group, m is 1 to 3, n is 4 to 16 and p is 1 to 3. Theinvention also covers acid addition salts.

The compounds of the above given formula can be classed as guanidatedN-(aminoalkyl)aminoalkanephosphonic acid derivatives and in the formulathe lower alkyl esters, half esters and also the alkali metal mono- ordi- salts are included.

The compounds are characteristic in that they contain both a phosphonicacid type group, ##STR3## and at least one guanidino group, ##STR4## andin that they are based on alkylene amines.

The pure compounds of the free phosphonic acids are fine whitecrystalline solids, and they are all soluble in water. The solubility inwater decreases somewhat with increasing chain lengths. The esters areless soluble in water but soluble in alcohols and other solvents. As arule the acid addition salts of the guanidated aminophosphonic acidcompounds are much more soluble in water than the free acids and alsomore soluble in alcohols.

Preferred compounds are those containing alkylene groups having from 4to 14 carbon atoms, and especially from 6 to 14 carbon atoms. Further,compounds of the general formula I given above wherein p equals 1 arepreferred, i.e. the compounds based on alkylene diamines. Compoundswherein m is 1 are preferred to those wherein m equals b 2 or 3.

It should be understood that when p is 2 or 3, n does not necessarilyhave to be the same for the different alkylene groups. These might ofcourse vary as a result of the use of technical amines having varyingchain lengths as starting material. It should further be understood thatwhen p is 2 or 3, either one, two or three of the Y-groups may beamidine groups, ##STR5## the rest being hydrogen. This depends on theguanidation reagent used in the preparation process and will bedescribed more in detail below. However, compounds wherein all groups Yare hydrogen are preferred.

The invention also relates to a method for the preparation of guanidatedN-(aminoalkyl)aminoalkanephosphonic acid derivatives of the above givenformula (I), said method comprising reacting a halogenoalkanephosphonicacid compound with an alkylene di- or polyamine and guanidation of theso obtained product.

The first step of the preparation method comprises reacting ahalogenoalkanephosphonic acid compound having the formula ##STR6##wherein Z and Z', as above, independent of each other are hydrogen, alower alkyl group having 1 to 4 carbon atoms or an alkali metal, and mis 1 to 3, preferably 1, and wherein X is a halogen, suitably chlorineor bromine and most preferably chlorine, with an alkylene di- orpolyamine of the formula.

    H.sub.2 N[(CH.sub.2).sub.n NH].sub.p (CH.sub.2).sub.n NH.sub.2,

wherein n is 4 to 16 and p is 0, 1 or 2. Diamines of this type aresuitably used as starting material.

The reaction between the halogenoalkanephosphonic acid compound and theamine is carried out in aqueous solution and at an elevated temperature.The temperature is suitably within the range of from 50° to 100° C. andpreferably from 70° to 100° C. The reaction rate will of course varywith the temperature and also with the starting materials; usually areaction time of up to about 20 hours will be sufficient. The reactioncan be carried out under reflux. After the reaction is completed waterand optionally excess of unreacted amine are removed, e.g. bydistillation, and the product is isolated.

The aminoalkylaminophosphonic acid derivatives of the general formula##STR7## are then guanidated using conventional guanidation reagentssuch as cyanamide, O-alkylisoureas, S-alkylisothioureas or salts ofthese etc. The temperature at the guanidation is not critical but mayvary within wide limits, from room temperature up to about 100° C. Theguanidation step is carried out under neutral or alkaline conditions andwhen the reaction is completed the reaction product solution isneutralized. The compounds can then be crystallized for isolation.

The above general preparation method applies to all the compounds. Asconcerns the acid addition salts these will vary with the guanidationreagent used and so will the number of guanidated amino groups. The acidaddition salt will further vary with the neutralizing agents used in theprocess. In the first reaction step the molar ratio of di- orpolyalkylene amine to halogenophosphonic acid compound is suitablywithin the range of from 2:1 to 8:1 and preferably within the range offrom 4:1 to 6:1. In the guanidation step it is usually sufficient tohave a ratio of 1:1 between the guanidation reagent and the amino groupsto be guanidated, although an excess of the guanidation reagent may beused.

As shown in the general formula I the novel compounds of the presentinvention may contain both guanidated primary and secondary aminogroups. Compounds containing one or several guanidated secondary aminogroups, i.e. those in which Y is an amidine group, may be prepared usingcyanamide as guanidation reagent. In contrast to the urea derivativescyanamide is an unspecific guanidation reagent and will randomlyguanidate both primary and secondary amino groups, while the ureas willpredominantly guanidate the primary amino groups.

The aminoalkylaminophosphonic acid compounds of the general formula (II)##STR8## wherein Z and Z', which may or may not be equal, are hydrogen,a lower alkyl group having 1 to 4 carbon atoms or an alkali metal, m is1 to 3, n is 4 to 16 and p is 1 to 3, which are intermediates in thepreparation of the guanidated aminophosphonic acid compounds, are noveland claimed per se. n is suitably 6 to 14.

The novel guanidated compounds of the present invention can be in theform of the free phosphonic acids or phosphonates or in the form of acidaddition salts. Both salts of mineral acids and organic acids can beprepared. When cyanamide is used as the guanidation reagent the acidaddition salt is suitably prepared by adding the desired acid in orafter the guanidation step and when ureas are used as guanidationreagents an isouronium compound or isothiouronium compound is selectedfor the preparation of acid addition salts. As examples of salts oforganic acids can be mentioned those of lower organic acids such asformates and acetates, those of higher organic acids such as oleates andstearates. Benzoates may also be used. The type of acid salt will ofcourse also have to be selected with respect to the intended use of thecompound in order not to have any negative effects in this use.

Particularly claimed compounds according to the invention are the novelcompounds of formula I wherein Z and Z' both are hydrogen, m is 1 or 2,n is 6 to 14 and p is 1 and the corresponding intermediates of formulaII wherein Z and Z' both are hydrogen, m is 1 or 2, n is 6 to 14 and pis 1.

The invention also covers the use of the guanidated aminophosphonic acidcompounds as biocides, and particularly as plant protecting agents,antimicrobial agents and insecticides. For this purpose it is in mostcases sufficient to use the crude reaction product resulting from thereaction between the halogenoalkanephosphonic acid or phosphonate andthe amine in the guanidation step without an intermediaterecrystallisation. The guanidated product will then contain the novelcompounds of the invention as the main component and the rest willconsist of guanidated di- or higher alkyleneamines and of intermediateunguanidated aminoalkylaminophosphonic acid compounds. Guanidated di- orhigher alkyleneamines are previously known to have biocidal effect andit has been found that the intermediate aminophosphonic acid compoundsof the present invention in some cases possess biocidal effect and thismakes it possible to utilize a crude reaction product. The products, orcompounds, can be formulated in conventional manner and used with inertcarriers or diluents. They may be useful in several areas; for exampleas bactericides, fungicides, insecticides, herbicides etc. The compoundsare particularly useful as fungicides both for industrial purposes, inwood treatment and especially as fungicides for agricultural andhorticultural purposes. The use of the compounds as fungicides inagriculture and horticulture, and especially as foliar fungicides is apreferred embodiment of the invention. It should also be mentioned thatthe compounds have other utilities; they might for example be used aschelating agents.

The invention is further illustrated in the following examples which,however, are not intended to limit the same.

EXAMPLE 1 A. Preparation of N-(12-aminododecyl)-aminomethanephosphonicmonohydrate. Compound 1 A.

Chloromethanephosphonic acid (15.1 g, 115.7 mmoles) and1,12-diaminododecane (100 g, 0.5 moles) were heated under reflux inwater (160 cm³) for 20 hours. The water was then distilled off andethanol (250 cm³) was added. The phosphonic acid was filtered off anddried. The crude yield was 30.7 g (85%). A sample was purified byrecrystallization from water/ethanol to giveN-(12-aminododecyl)-aminomethanephosphonic acid monohydrate as a finewhite crystalline solid having a melting point of 234° C.

B. Preparation of N-(12-guanidinododecyl)-aminomethanephosphonic acidmonohydrate. Compound 1 B.

N-(12-aminododecyl)-aminomethanephosphonic acid monohydrate (2.5 g, 8mmoles), sodium hydroxide (1.3 g, 38 mmoles) and S-methylisothiouroniumchloride (2.0 g, 16.4 mmoles were dissolved in water (120 cm³) andheated at 90° C. for 4 hours. The solution was acidified to pH 1 withhydrochloric acid and evaporated. Methanol (100 cm³) was added andsodium chloride was filtered off. The filtrate was neutralized to pH 6with propylene oxide. The solid so formed was filtered off and washedwith methanol (50 cm³).

The crude yield after drying of guanidinophosphonic acid was 2.6 g(91%). A sample was recrystallized from hot water to giveN-(12-guanidinododecyl)-aminomethanephosphonic acid monohydrate as afine white crystalline solid having a melting point of 129°-130° C.

EXAMPLE 2 A. Preparation of N-(6-aminohexyl)-aminomethanephosphonic acidmonohydrate. Compound 2 A.

Chloromethanephosphonic acid (6.5 g, 49.8 mmoles) and 1.6-diaminohexane(34.8 g, 300 mmoles) were dissolved in water (130 cm³) and heated underreflux for 20 hours. The water was removed and ethanol (250 cm³) wasadded to the solid residue. The phosphonic acid was filtered off anddried. The crude yield was 10.4 g (92%). A sample was purified byrecrystallization from water/ethanol to giveN-(6-aminohexyl)-aminomethanephosphonic acid monohydrate as a fine whitecrystalline solid having a melting point of 235° C.

B. Preparation of N-(6-guanidinohexyl)-aminomethanephosphonic acidmonohydrate. Compound 2 B.

N-(6-aminohexyl)-aminomethanephosphonic acid monohydrate (6.1 g, 26.7mmol), sodium hydroxide (4.15 g, 104 mmoles) and S-methylisothiouroniumchloride (6.3 g, 49.8 mmoles) were dissolved in water (50 cm³) andheated at 60° C. for 4 hours. The solution was acidified to pH 1 withhydrochloric acid and evaporated. Methanol (50 cm³) was added and sodiumchloride was filtered off. The filtrate was neutralized to pH 6 withpropylene oxide.

The sticky precipitate was dissolved in cold water (50 cm³) and acetoneadded dropwise until the solution just became opaque. A few drops ofwater were added to clear the solution which was then stored in a fridgefor several days. The crystals formed were filtered off, washed withacetone and dried in a vacuum oven at 60° C. to yieldN-(6-guanidinohexyl)-aminomethanephosphonic acid monohydrate (4.3 g,60%) as a fine white crystalline solid having a melting point of 182° C.

EXAMPLE 3 A. Preparation of N-(10-aminodecyl)-aminomethanephosphonicacid monohydrate. Compound 3 A.

Chloromethanephosphonic acid (5.5 g, 42 mmoles) and 1.10-diaminodecane(44 g, 255 mmoles) were heated under reflux in water (200 cm³) for 20hours. The water was removed and ethanol (400 cm³) added to the solidresidue. The phosphonic acid was filtered off and dried. The crude yieldwas 11.4 g (87%). A sample was purified by recrystallization fromwater/ethanol to give N-(10-aminodecyl)-aminomethanephosphonic acidmonohydrate as a fine white crystalline solid having a melting point of238° C.

B. Preparation of N-(10-guanidinodecyl)-aminomethanephosphonic acidmonohydrate. Compound 3 B.

N-(10-aminodecyl)-aminomethanephosphonic acid monohydrate (4.1 g, 14.4mmoles), S-methylisothiouronium chloride (3.65 g, 28.9 mmoles) andsodium hydroxide (2.8 g, 70 mmoles) were dissolved in water (100 cm³)and heated in an oil bath at 70° C. for 4 hours. The clear solution wasthen acidified to pH 1 with concentrated hydrochlorid acid and thevolatile components were removed on a rotary evaporator. The oilyresidue was dissolved in methanol (100 cm³) and sodium chloride filteredoff (3.4 g, 83%). Propylene oxide was then added to the filtrate untilpH 6.

The crude guanidinophosphonic acid was washed with methanol (50 cm³) anddried. The yield was 4.2 g (89%). Recrystallization from water/acetoneand drying at 60° C. gave N-(10-guanidinodecyl)-aminomethanephosphonicacid monohydrate (3.8 g, 81%) as a fine white crystalline solid having amelting point of 133°-134° C.

EXAMPLE 4 A. Preparation of N-(8-aminooctyl)-2-aminoethanephosphonicacid monohydrate. Compound 4 A.

Diethylbromoethanephosphonate (15.3 g, 0.062 moles) and1.8-diaminooctane (54.0 g, 0.375 moles) were heated under reflux inwater (250 cm³) for 5 hours. The water and excess diamine were thendistilled off. Concentrated hydrochloric acid (280 cm³) was added andthe solution heated under reflux for 8 hours. The solution was thenevaporated to dryness on a rotary evaporator and the residue wasdissolved in methanol (75 cm³) and propylene oxide wad added to pH 6.The phosphonic acid was filtered off and dried. The crude yield was 10.2g (60.5%). A sample was purified by recrystallization from water/ethanolto give N-(8-aminooctyl)-2-aminoethanephosphonic acid monohydrate as afine white crystalline solid having a melting point of 210° C.

B. Preparation of N-(8-guanidinooctyl)-2-aminoethanephosphonic acidmonohydrate. Compound 4 B.

N-(8-aminooctyl)-2-aminoethanephosphonic acid monohydrate (4.0 g, 0.0148moles), S-methylisothiouronium chloride (3.75 g, 0.0296 moles) andpotassium hydroxide (3.32 g, 0.0592 moles) were dissolved in water (60cm³) and heated in an oil bath at 80° C. for 4.5 hours. The clearsolution was then acidified to pH 2 with concentrated hydrochloric acidand the volatile components were removed on a rotary evaporator. Theoily residue was dissolved in methanol (75 cm³) and potassium chloridefiltered off (3.5 g, 79.3%). Propylene oxide was then added to thefiltrate until pH 6. The sticky precipitate was dissolved in cold water(50 cm³) and acetone added dropwise until the solution just becameopaque. A few drops of water were added to clear the solution which wasthen stored in a fridge for several days. The crystals formed werefiltered off, washed with acetone and dried in a vacuum oven at 60° C.to yield N-(8-guanidinooctyl)-2-aminoethanephosphonic acid monohydrate(2.7 g, 58.4%) as a fine white crystalline solid having a melting pointof 108° C.

EXAMPLE 5 A. Preparation of N-(8-aminooctyl)-aminomethanephosphonic acidmonohydrate. Compound 5 A.

Chloromethanephosphonic acid (7.5 g, 58 mmoles) and 1.8-diaminooctane(50.0 g, 347 mmoles) were dissolved in water (130 cm³) and heated underreflux for 20 hours. The water was then removed and ethanol (250 cm³)added to the solid residue. The phosphonic acid was filtered off anddried. The crude yield was 13.3 g (90%). A sample was purified byrecrystallization from water/ethanol to giveN-(8-aminooctyl)-aminomethanephosphonic acid monohydrate as fine whitesolid having a melting point of 242° C.

B. Preparation of N-(8-guanidinooctyl)-aminomethanephosphonic acidmonohydrate. Compound 5 B.

N-(8-aminooctyl)-aminomethanephosphonic acid monohydrate (5.6 g, 21.9mmoles), S-methylisothiouronium chloride (5.53 g, 43.7 mmoles) andpotassium hydroxide (4.9 g, 87.3 mmoles) were dissolved in water (50cm³) and heated in an oil bath at 60° C. for 4 hours. The solution wascooled and acidified to pH 1 with concentrated hydrochloric acid. Thevolatile components were removed on a rotary evaporator and methanol (50cm³) added to the residue. Potassium chloride (5.9 g, 80% after drying)was filtered off and propylene oxide added to the filtrate until pH 6.

The supernatant liquors were decanted off from the oil formed onaddition of the propylene oxide and the oil washed with methanol (50cm³). Acetone (75 cm³) was added and the solvents removed on a rotaryevaporator. The solid so formed was dried in a vacuum oven at 60° C. (5hours), to give crude guanidinophosphonic acid (5.8 g, 89%).Recrystallization from water/acetone gaveN-(8-guanidinooctyl)-aminomethanephosphonic acid monohydrate (3.9 g,60%) as a fine white crystalline solid having a melting point of 170° C.

EXAMPLE 6 A. Preparation of N-(4-aminobutyl)-aminomethanephosphonic acidmonohydrate. Compound 6 A.

Chloromethanephosphonic acid (7.0 g, 53.6 mmoles) and 1,4-diaminobutane(30.0 g, 340 mmoles) were heated under reflux in water (200 cm³) for 20hours. The water was then distilled off and acetone (110 cm³) was added.The phosphonic acid was filtered off and dried. The crude yield was 9.8g (91%). A sample was purified by recrystallization from water/ethanolto give N-(4-aminobutyl)-aminomethanephosphonic acid monohydrate as afine white crystalline solid having a melting point of 258° C.

B. Preparation of N-(4-guanidinobutyl)-aminomethanephosphonic acidmonohydrate. Compound 6 B.

N-(4-aminobutyl)-aminomethanephosphonic acid monohydrate (3.8 g, 19mmoles), sodium hydroxide (3.0 g, 76 mmoles) and S-methylisothiouroniumchloride (4.8 g, 38 mmoles) were dissolved in water (50 cm³) and heatedat 70° C. for 4 hours. The solution was acidified to pH 1 withhydrochloric acid and evaporated. Methanol (100 cm³) was added andsodium chloride was filtered off. The filtrate was neutralized to pH 6with propylene oxide. The sticky precipitate was dissolved in a minimumof cold water and acetone added dropwise until the solution just becameopaque. A few drops of water were added to clear the solution which wasthen stored in a fridge for several days. The crystals formed werefiltered off, washed with acetone and dried in a vacuum oven at 60° C.to yield N-(4-guanidinobutyl)-aminomethanephosphonic acid monohydrate(2.9 g, 63%) as a fine white crystalline solid having a melting point of160°-161° C.

EXAMPLE 7 Preparation of N-(9-aminononyl)aminomethanephosphonic acidmonohydrate. Compound 7A.

Chloromethanephosphonic acid (4.0 g, 30.6 mmoles) and 1.9-diaminononane(20.1 g, 127.2 mmoles) were dissolved in water (100 cm³) and theresultant solution heated under reflux for 20 hours. The water was thendistilled off and methanol (80 cm³) added to the residue. The solid wasfiltered off, washed with methanol (2×50 cm³) and dried in a vacuum ovenat 60° C. for three hours to yield the crudeN-(9-aminononyl)aminomethanephosphonic acid monohydrate (6.5 g, 78.5%),having a melting point of 240°-241° C.

EXAMPLE 8 Preparation of the di-potassium salt ofN-(8-guanidino-octyl)aminomethanephosphonic acid. Compound 8.

N-(8-guanidino-octyl)aminomethanephosphonic acid monohydrate (3.0 g,10.07 mmoles) and potassium hydroxide (1.13 g, 20.14 mmoles) weredissolved in water (100 cm³). The water was then distilled off andmethanol (80 cm³) added to the residue. Filtration and then evaporationof the methanol, followed by drying in a vacuum oven at 60° C. for threehours gave the crude di-potassium salt as a white solid (2.7 g, 71.7%).

Identification of compounds

The structures of the compounds were ascertained by nuclear magneticresonance (¹ H-, ¹³ C-, ¹⁵ N- and ³¹ P-) spectra and mass spectra. Allcompounds give very strong (M+1)⁺ -peaks (in most cases the base peak)using FAB-(Fast Atom Bombardment) mass spectrometry, see below

    ______________________________________                                        Compound     Molecular weight                                                                           (M + 1).sup.+                                       ______________________________________                                        1A           294          295                                                 2A           210          211                                                 3A           266          267                                                 4A           252          253                                                 5A           238          239                                                 6A           182          183                                                 1B           336          337                                                 2B           252          253                                                 3B           308          309                                                 4B           294          295                                                 5B           280          281                                                 ______________________________________                                    

EXAMPLE 7 Fungicidal activity test

Compounds prepared as above were screened for their fungicidal activity.

The fungicidal activity of the substances was examined using a mycelialgrowth inhibition test on agar according to the following method.

The substances were dissolved in sterilized potatoe dextrose agar (PDA)to give concentrations of 500 and 1000 ppm respectively. The mixtureswere then poured onto standard petri dishes with 9 cm diameter. A 5 mmdiameter agar plug with lively growing mycelia (cultivated on PDA) wasplaced in the center of each petri dish. After incubation at +28° C. for7 to 21 days (depending on the growth rate of the respective fungus) thegrowth diameter was measured and compared with that of untreated dishes.

Several plant pathogenic fungi belonging to different subdivisions andrepresentative of important crop diseases were used in the tests.

In the tables below the results are shown by classifying the compoundsaccording to the following scale: 0=0-25% inhibition of growth, 1=26-50%inhibition of growth, 2=51-75% inhibition of growth, 3=76-99% inhibitionof growth, 4=100% inhibition of growth.

                  TABLE 1                                                         ______________________________________                                                  Dosage                                                                              Efficacy of Compound                                          Fungus      (ppm)  1 B         3 B  5 B                                       ______________________________________                                        Pyricularia 500     1          4    2                                         oryzae                                                                        Botrytis    500     3          4    0                                         cinerea                                                                       Rhizoctonia 500     1          1    0                                         solani                                                                        Rhizoctonia 1000    4          2    n.t.                                      solani                                                                        Septoria    500     1          4    1                                         nodorum                                                                       Septoria    1000    2          4    2                                         nodorum                                                                       Drechslera  500     3          4    n.t.                                      sativa                                                                        Drechslera  1000    3          4    3                                         sativa                                                                        Fusarium    1000    2          2    n.t.                                      avenaceum                                                                     ______________________________________                                         Note:                                                                         n.t. = not tested                                                        

                                      TABLE 2                                     __________________________________________________________________________                     Efficacy of Compound                                         Fungus   Dosage (ppm)                                                                          1A 2A 3A 4A 5A 6A 2B 4B                                      __________________________________________________________________________    Drechslera sativa                                                                      500     n.t.                                                                             n.t.                                                                             3  3  n.t.                                                                             n.t.                                                                             n.t.                                                                             2                                        "       1000    4  2  3  3  2  2  2  n.t.                                    Septoria nodorum                                                                       500     0  3  1  0  0  2  n.t.                                                                             0                                       __________________________________________________________________________     Note:                                                                         n.t. = not tested                                                        

We claim:
 1. Guanidated N-(aminoalkyl)aminoalkanephosphonic acidderivatives having the general formula ##STR9## wherein Z and Z', whichmay or may not be equal, are hydrogen, a lower alkyl group having 1 to 4carbon atoms or an alkali metal, Y is hydrogen or an amidine group, m is1 to 3, n is 4 to 16 and p is 1 to 3, or their acid addition salts. 2.Compounds according to claim 1, wherein p is
 1. 3. Compounds accordingto claim 1, wherein m is
 1. 4. Compounds according to claim 1, wherein Zand Z' are hydrogen.
 5. Use of guanidatedN-(aminoalkyl)aminoalkanephosphonic acid derivatives having the generalformula ##STR10## wherein Z and Z', which may or may not be equal, arehydrogen, a lower alkyl group having 1 to 4 carbon atoms or an alkalimetal, Y is hydrogen or an amidine group, m is 1 to 3, n is 4 to 16 andp is 1 to 3, or their acid addition salts, as biocides.